Age related macular degeneration (AMD) is the leading cause of legal blindness in the developed world and the most common geriatric eye disorder. AMD is characterized by degeneration of the neuroepithelium in the macular area of the eye. Two main advanced forms of AMD may be distinguished: neovascular AMD and atrophic AMD.
Neovascular AMD, also referred to as “exsudative” or “wet” AMD is characterized by the invasion of abnormal choroidal (or occasionally retinal) blood vessels and fluid leakage into the retina, a phenomenon also referred to as “choroidal neovascularization” or “CNV”. Neovascular AMD is the leading cause of blindness among the elderly in industrialized nations and several treatments were developed and shown to improve the clinical situation of the treated patients, especially through therapies targeting VEGFA, a potent stimulator of angiogenesis and vasopermeability.
Atrophic AMD, also referred to as “geographic atrophy” or “GA”, “end-stage dry” AMD or “dry” AMD, affects the macula area, in which the retinal pigmented epithelium can no longer support photoreceptor function owing to spontaneous degeneration of large confluent regions. The incidence of atrophic AMD and neovascular AMD are comparable, but the expansion of the atrophic lesions and associated visual impairment is usually a slower process. No currently approved therapies are available to this date for preventing or curing geographic atrophy, mainly as a result of the lack of identification of suitable molecular targets. Some studies have demonstrated that consumption of vitamin E and C, of betacaroteinoids and Zinc may slow the development of atrophic DMLA, but the progression of the disease is unfortunately not stopped.
Several studies have established that the subretinal space located between the retinal pigmented epithelium and the photoreceptor outer segments is a zone of immune privilege mediated by immunosuppressive retinal pigmented epithelium signals. Nevertheless, mononuclear phagocytes (comprising a family of cells that include microglial cells, monocytes and macrophages) were shown to accumulate in the subretinal space in the advanced forms of sight-threatening AMD: i.e. CNV and geographic atrophy. Whereas subretinal migration of microglial cells appear to be required for eliminating visual by-products and to maintain vision, the accumulation thereof as well as of macrophages in the subretinal space was purported to result in a destructive inflammation possibly involved in AMD development (Gupta et al., 2003. and Kohno et al., 2013).
Further, increased levels of inflammation mediator proteins such as interleukin 6 (IL-6) have been measured in the serum of patients suffering from AMD (Klein et al., 2008 and Seddon et al., 2005). Nevertheless, these studies failed to identify or even suggest specific molecular targets for preventing and/or treating AMD, and more specifically atrophic AMD. Whereas EP 1 990 060 has disclosed the use of IL-6 antagonists for treating the neovascular form of AMD, this document contains no indication nor suggestion that IL-6 antagonists might exert any beneficial effect on patients suffering from the atrophyic form of AMD. In addition, WO2004/045507 discloses the use if IL-6 antagonists for treating diseases/conditions associated with pathological angiogenesis, such as for example wet AMD, since this disease is characterized by an abnormal development of choroidal neovascularization. By no mean, WO2004/045507 can be regarded as describing treatment of dry AMD, since it does not rely to neovascularization deficiencies or abnormalities. Similarly, EP2116530 discloses a novel pyrrole derivative having an inhibitory activity against IL-6 production and/or inhibitory effect on choroidal neovascularization, and by no mean relates to the treatment of diseases not involving neoangiogenesis, such as dry AMD.
Methods for treating drusen comprising administering active ingredients such as imatinib mesylate, ponatinib, bosutanib, DAPT and bexarotene are also disclosed in WO2013/148183. Drusen are extracellular deposits that accumulate between the retinal pigmented epithelium and the Bruch membrane. They are composed of aggregated intracellular, extracellular and secreted proteins, and lipids and cellular components. As demonstrated in WO2013/148183, APOE notably amounts within the major components of human drusen. WO2013/148183 suggests that treating cells with the above listed active ingredients results in a decrease of APOE levels, among others, in drusen, and establishes a link between the treatment of drusen and the treatment of atrophic AMD. Nevertheless, this document actually fails to demonstrate unambiguously that an actual effect of the tested active ingredients is obtained on APOE expression and accumulation in drusen. Further, the causal relationship established between atrophic AMD and drusen in this document is clearly invalidated by several publications within this field (see for instance Klein et al., 2007, which demonstrates that drusen may only be regarded as providing an increased risk to develop AMD, but should in no manner be considered as a symptom of atrophic AMD).
In view of these elements, there is therefore still an ongoing need for identifying active ingredients for preventing and/or treating retinal inflammation, and more particularly atrophic AMD.
This objective is reached by the present invention, since the inventors have surprisingly demonstrated that increased amounts of APOE induce IL-6 expression, which in turn downregulates the reticulum pigmented epithelium-expressed FasL. The inventors demonstrated that diminished FasL expression then enables prolonged subretinal mononuclear phagocytes survival, age-dependent mononuclear phagocyte accumulation, and associated photoreceptor degeneration. These findings revealed a pro-inflammatory function of APOE, which is in total contrast with its well-known anti-inflammatory role in other pathological contexts. Inventors have thus surprisingly established that inhibiting excess APOE and IL-6 in retinal inflammation and more particularly in dry AMD and retinitis pigmentosa results in preventing and/or curing the inflammation and thereby preventing the photoreceptor degeneration.